1. Field of the Invention
The present invention relates to improvements in apparatus and methods for processing biological liquids, e.g., blood samples, based on measurements made during the transport of such liquids to a liquid-processing station. More particularly, it relates to improvements in apparatus and methods for adjusting a liquid-processing procedure, for example, a procedure for producing a blood-smear atop a microscope slide or the like, based on an “in-transit” measurement related to the coating characteristics of such liquids.
2. The Prior Art
In the analysis of whole blood samples, various automated flow-cytometric instruments (e.g., hematology and fluorescence flow cytometry instruments) are commonly used to differentiate and enumerate the various sub-populations of red and white blood cells comprising a unit volume of sample. Such instruments operate in a known manner to differentiate each of the sample cells by causing the cells to pass, one-at-a-time, through a cell-interrogation zone of the instrument. While passing through this zone, each cell is counted and “typed,” typically through a combination of physical, electrical and/or optical measurements made substantially simultaneously on the cell. In the event the measured and calculated values provided by these clinical instruments are within “normal” limits, no further sample analysis is usually required, and the results are reported accordingly. However, in the event the sample analysis indicates an abnormality in the sample, either in terms of the number of cells of a particular sub-population, or in the level of a measured or calculated sample parameter, a visual inspection of the sample may be required to complete the analysis. Such an inspection is commonly effected by depositing a drop of sample on a microscope slide, and spreading or “smearing” the drop across the slide surface with a straight-edged smearing member (typically the edge of another microscope slide) to produce a “blood-smear” that can be manually analyzed under a microscope. Ideally, the blood-smears are of uniform length, and each comprises a monolayer of cells. In such a layer, all cells on the slide are visible under a microscope, with none obscuring another.
While blood-smears of the above type are often produced manually, they often vary dramatically in quality, depending on the skill of the technician. Thus, various automated slide-making instruments have been devised which take much of the “guess-work” out of the smear-producing process. One such slide-maker is the Model Gen*S™ Slidemaker, manufactured and sold by Beckman Coulter, Inc., Fullerton, Calif. Details of this instrument are described in the commonly assigned U.S. Pat. No. 5,650,332 issued in the names of Gao and Sperber. This particular slide-maker is actually an accessory instrument that is designed to be used with a “host” hematology instrument, i.e., the Model Gen*S™ Blood Analyzer, also made by Beckman Coulter, Inc. In addition to counting and differentiating red cells, white cells and platelets in the blood sample, the host instrument operates to measure or calculate several other blood sample characteristics, including the hematocrit (HCT) of the sample, the hemoglobin concentration (Hgb) of the sample's red blood cells, the red blood cell indices (RBCI), and the red cell distribution width (RDW). Based on the values of up to eight different sample parameters determined by the host instrument, the slide-making instrument acts to calculate (using a relatively complex algorithm containing such parameters) a “motion profile” that controls the acceleration and velocity of a drop-smearing member used to spread a blood drop atop the microscope slide in order to achieve a desired blood-smear thickness and length. The algorithms used by the Gen*S Slidemaker attempt to predict how blood components will interact with each other when the blood is smeared. As indicated above, the ideal thickness of the blood smear is that which provides a monolayer of cells, and a desired nominal smear length (e.g., about 1.4 inches for a standard microscope slide). While this approach to automated slide-making produces blood smears with relatively good precision and reproducibility, it will be appreciated that it does not lend itself to use in a stand-alone slide-maker in which a blood smear is to be made without a prior sample analysis by another instrument.
In U.S. Pat. No. 5,209,903 to Kanamori et al., another multi-instrument blood analysis system is disclosed. One component of such system is an “automatic blood smear-generator” that includes a relatively simple apparatus for measuring the “viscosity” of the blood sample being processed. Here, the viscosity information is used to control the smear-making process; in this case, it is used to control the size of the blood drop to be smeared, the angle of a smearing blade, and/or the velocity of the smearing blade. The viscosity measurement is made while a portion of the blood sample is being transported through tubing from a test tube containing the sample to a blood-drop-dispensing needle. Specifically, a syringe pump is used to aspirate the blood sample into the transport tubing. As the blood moves through the tubing, each of a pair of photo-sensors positioned at spaced locations along the tubing length produces a timing signal as the forward-most surface of the aspirated blood sample passes by. Since a more viscous (thicker) blood sample will flow at a slower rate through the tubing than a less viscous (thin) blood sample for a given syringe force, the elapsed time between the production of the two timing signals will indicate the viscosity of the blood sample. The longer the elapsed time between the timing signals, the higher the sample viscosity; and vice versa. A high viscosity determination operates to reduce the rate of movement of the smearing blade in order to achieve a desired blood smear thickness and length. Conversely, a low viscosity determination will cause the smearing blade to be advanced at a faster rate. While, this scheme of adjusting the blood-smearing process on the basis of a viscosity measurement may enhance the uniformity of blood smears for a some types of blood samples, it does not necessarily do so for a wide variety of blood samples. As may be appreciated, the speed at which a sample liquid can be made to pass through a tube is not necessarily indicative of how well such sample will coat a supporting substrate after being spread thereon. For example, a drop of mercury cannot be uniformly spread atop a substrate not matter what its viscosity or the speed of the smearing blade. The surface tension of liquid mercury is simply too great to allow such spreading. Similarly, attempting to smear a drop of liquid atop a highly polished or adhesive surface is likely to fail if the frictional forces between the liquid and the surface are too low. Thus, it will be appreciated that viscosity of a blood sample is only one of several factors at work in determining the quality of a blood smear.
An “idealized method” for achieving uniformity in the production of blood smears would be to perform two successive blood smears, i.e., a “test smear” followed by the “final smear.” By measuring the smear length and/or the smear thickness of the test smear, the motion profile of the drop-spreading member can be adjusted to produce substantially uniform final smears. But, this approach would be problematic in that it is wasteful of blood, it requires the use of two slides, and it significantly reduces throughput of the slide-making instrument.